INH toxicity

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Background

  • INH used for latent and active TB treatment

Toxicology

  • Isoniazid’s metabolites restrict the conversion of pyridoxine to pyrodoxal-5’-phosphate and binds to pyridoxine, facilitating its excretion in the urine
  • Loss of pyridoxine leads to decreased GABA synthesis due to the decreased function of glutamic acid decarboxylase (GAD)
  • Anion-gap acidosis likely results from lactic acid buildup as a consequence of persistent seizure activity
  • Finally come due to decreased catecholamine synthesis secondary to pyridoxine depletion

Toxic Dose

  • 2-3g ingested can lead to symptoms, 10-15g can lead to death[1]

Pharmacology

  • Absorbed via GI tract (small intestine), peak concentrations at 1-2 hours after ingestion
  • Volume of Distribution: 0.6L/kg

Metabolism

  • Clearance of 46mL/min, metabolized by acetylation.
    • T1/2 for fast acetylators = 70 minutes
    • T1/2 for slow acetylators = 3 hours

Excretion

  • Via kidneys with levels successfully measured in urine[1]

Clinical Features

Signs and Symptoms

  • Seizure
  • Metabolic Acidosis
  • Coma
  • Signs and symptoms can appear 30 minutes after ingestion, with more severe symptoms including persistent seizures, metabolic acidosis, and coma
  • Hepatotoxicity
    • Most common side effect and more frequent with slow acetylators, the elderly, and those with preexisting liver disease
    • Approximately 20% of patients on isoniazid therapy can have elevated liver enzymes
    • Treatment is stopped when levels reach three times the upper limit of normal with symptoms or five times the limit of normal without[1][2]

Evaluation

  • Seizures refractory to conventional treatment are hallmarks of isoniazid toxicity
  • Clinical history is extremely important in evaluating for isoniazid toxicity (i.e. dosing history, duration of treatment, estimated dose taken)
  • Elevated anion-gap metabolic acidosis with elevated lactate in the appropriate clinical setting AND refractory seizures should raise suspicion
  • INH levels can be measured but results may not immediately be available [1]

Management

  • Focus is on aggressive supportive care and hemodynamic stabilization Focuses mainly on management of symptoms and stabilization of patient.

Activated Charcoal

  • If ingestion occurred within an hour of presentation, activated charcoal with cathartics may be necessary to restrict absorption and to facilitate excretion via the GI tract

Benzos

  • May not be effective but will activate the GABA receptors and halt seizure activity

Pyridoxine

  • Known INH quantity ingested treat with with a 1:1 ingested isoniazid:administered pyridoxine dose ratio
  • Unknown INH quantity ingested treat with empiric 5g of pyridoxine can be administered
  • Children - start 70-300mg/kg and increase until seizure resolves[3]
  • IV Infusion rate is 0.5 g/min until the seizures stop or the maximum dose is reached. Remainder of dose infused over 4 to 6 hours
  • Pyridoxine administration may temporarily worsen the metabolic acidosis
  • Hemodialysis can clear lactate and isoniazid from the bloodstream effectively and can be used as a final measure to increase clearance if needed. [1]

Disposition

  • Patient will likely require admission and potentially ICU care for continued monitoring and evaluation
  • If the patient has active TB also keep in respiratory isolation

See Also

References

  1. 1.0 1.1 1.2 1.3 1.4 Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th Ed. Chapter 55: Isoniazid.
  2. Gent, WL et al. Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients. Eur J Clin Pharmacol (1992) 43: 131-136.
  3. Minns, A. et al. Isoniazid-Induced Status Epilepticus in a Pediatric Patient After Inadequate Pyridoxine Therapy. Pediatric Emergency Care. 2010:26(5)380-381

Authors:

Neil Young